The goals of this project are to continue to refine a template for the molecular basis of cannabinoid psychopharmacological activity, to establish a template for the analgesic activity of the cannabinoids, and to use both of these templates to provide a basis for the design of cannabinoid analgesics with reduced psychopharmacological liability. The theoretical work proposed here will be supported, supplemented, and probed by collaborative studies with experimentalists. Hypotheses which result from the theoretical studies will form the basis for the synthesis of new analogs and their evaluation in experiments in behavioral pharmacology. The research plan has been designed to test the following hypotheses: (1) that the basis of psychopharmacological activity in these compounds is the set of molecular properties conferred by the lone pairs of electrons of the phenol oxygen and by the orientation of the carbocyclic ring with respect to the pheonol group, (2) that the basis of analgesic activity in these compounds is the set of molecular properties conferred by the presence and relative location of two negative potential regions in the top half of the cannabinoid analgesic molecule, (3) that separation of these two activities may be achieved in cannabinoids which possess negative potentials in the correct regions to mimic the analgesia template but whose carbocyclic rings are not in the correct orientation to produce psychoactivity. To this end eleven cannabinoids which possess psychopharmacological activity in varying degrees and eight cannabinoids which possess analgesic activity in varying degrees will be examined. The theoretical methods employed here permit the accounting for the pharmacological activity/inactivity of cannabinoids which are structurally dissimilar, as well as of cannabinoids which are structurally very similar. In order to make possible this analysis of disparate classes of cannabinoids, the requirements for each activity are formulated by molecular reactivity characteristics that are independent of atom-to-atom resemblances. Such characteristics include the molecular electrostatic potential and the accessible molecular surface of these compounds calculated in the preferred molecular conformation and in conformations defined by hypotheses on their mode of interaction with specific targets (e.g. receptors). The results of these studies should contribute to an understanding of the actions of the cannabinoids at the molecular level.